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Utah Medicaid Pharmacy & Therapeutics Committee Drug Utah Medicaid Pharmacy & Therapeutics Committee Drug Class Review Antidepressants, Monoamine Oxidase Inhibitors (MAOIs) 28:16:04.12 Isocarboxazid (Marplan®, generic) Phenelzine (Nardil®, generic) Selegiline (EmSam®) Tranylcypromine (Parnate®, generic) Anti-Parkinson Agents, Monoamine Oxidase B Inhibitors (MAO-B) 28:36.32 Rasagiline (Azilect®) Selegiline (Eldepryl®, Zelapar® and generic-for some products) Final Report September 2016 Review Prepared by: Vicki Frydrych, PharmD, BS, Clinical Pharmacist Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy Copyright © 2016 by University of Utah College of Pharmacy Salt Lake City, UT. All rights reserved. 1 Table of Contents Executive Summary ........................................................................................................................ 3 Introduction: .................................................................................................................................... 5 Table 1: Comparison of Monoamine Oxidase Inhibitor Antidepressants .................................. 6 Disease Overview ........................................................................................................................... 9 Table 2. Current Clinical Practice Guidelines for the Treatment of Depressive Disorders ...... 11 Table 3. Current Clinical Practice Guidelines for the Treatment of Parkinson’s Disease ........ 17 Pharmacology ............................................................................................................................... 22 Table 4: Pharmacokinetics of Tricyclic (and Tetracyclic) Antidepressants ............................. 25 Special Populations ....................................................................................................................... 27 Table 5: Special Populations ..................................................................................................... 28 Methods......................................................................................................................................... 30 Evidence ........................................................................................................................................ 30 Summary: ...................................................................................................................................... 38 Refernces....................................................................................................................................... 41 2 Executive Summary Introduction: This review includes the nonselective monoamine oxidase inhibitors isocarboxazid, phenelzine and tranylcypromine, labeled for use in the treatment of depression as well as the specific monoamine oxidase-B inhibitors (MAO-B) selegiline and rasagiline. Indicated for the treatment of depression, the non-specific monoamine oxidase inhibitors are available in tablet formulation as are the MAO-B medications. Selegiline is additionally available in transdermal formulation (EmSam®) for use in depression. Both MAO-B inhibitors (rasagiline and selegiline) are indicated for the treatment of Parkinson’s disease. Rasagiline is available as an oral tablet and selegiline is available as oral tablet, capsule and orally disintegrating tablet formulations. The transdermal formulation of selegiline is not labeled for use in Parkinson’s disease. Monoamine oxidase inhibitors (MAOIs) have been available for use for over 60 years following the discovery that the antitubercular drug iproniazid had mood-elevating properties. MAOIs are categorized in a variety of ways. By chemical structure they are either hydrazine (phenelzine, isocarboxazid) or non-hydrazine (rasagiline, selegiline and tranylcypromine) compounds. By MAO enzyme selectivity, they demonstrate MAO-A, MAO-B or mixed selectivity. Categorized by enzyme binding affinity they demonstrate either reversible or functionally irreversible binding to monoamine enzymes. MAOIs are highly active antidepressants, however their use has been limited by a number of coincident occurrences. First, the FDA required efficacy studies on medications marketed before the 1960s, including the MAOIs. At this same time, morbidity and mortality reports were being published that found the MAOIs “unsafe”, although the connection with tyramine intake, which could be controlled, was not known. Finally, a study of the Medical Research Council in 1965 compared a (too) low dose of phenelzine (60 mg daily) over a too short duration (4 weeks) with a new tricyclic (imipramine) in inpatients with severe endogenous depression and found imipramine to have superior efficacy. Imipramine also appeared better tolerated, albeit the TCA side effect profile had not been fully defined. These events are most responsible for the current disuse of the MAOIs. By the 1970s, investigators identified MAO subtypes, MAO-A and MAO-B. MAO-B degrades dopamine and was found in high concentration in the basal ganglia of the brain. MAO- B inhibition resulted in increased dopamine concentrations in the brain and these agents began to find their utility in the treatment of Parkinson’s disease, a disease of brain dopamine deficiency. Clinical Efficacy: Evidence is insufficient to identify differences in efficacy between MAOIs. A review of the evidence finds that comparative evidence between MAOIs or MAO-Bs is scarce. In the treatment of depression, MAOI efficacy appears to persist for at least 6 months. Available evidence suggests that phenelzine may be superior to isocarboxazid in inpatient treatment of depression while no difference was found between phenelzine and tranylcypromine in treatment-resistant depression. Evidence suggests that compared to TCAs, MAOIs may be especially useful in the treatment of atypical depression. Although efficacious in the treatment of bulimia nervosa and social anxiety disorders comparative evidence is unavailable. Evidence does not support the use of MAOIs in smoking cessation. There are no comparative trials with selegiline transdermal therapy for depression. Rasagiline was found efficacious in the treatment of Parkinson’s disease fatigue although comparative evidence is unavailable. Evidence found no increase in mortality with use of MAO-B agents in the treatment of Parkinson’s disease. 3 Comparative evidence is lacking for MAO-B therapies in Parkinson’s disease. MAO-B therapy was not more effective than other anti-Parkinson therapies, but may be better tolerated. Adverse Drug Reactions: MAOIs may increase the risk of suicidality in young people and may activate mania/hypomania in patients with undiagnosed bipolar disorder. Rapid discontinuation of MAOI therapy may precipitate a withdrawal reaction. Early adverse events include postural hypotension which may be minimized with slow dose uptitration, administration of fluids, divided or bedtime dosing. Late adverse effects include weight gain, paresthesias (which may be minimized with pyridoxine supplementation), hypoglycemia, tremor and blood dyscrasias. MAOIs (especially maprotiline) lower the seizure threshold and should be used cautiously in patients with a history or risk of seizures. Although rare, hepatotoxicity may occur (especially with phenelzine and isocarboxazid) and patients should be instructed to note and report signs and symptoms of hepatotoxicity. Transdermal selegiline may cause application site reactions, problems with impulse control, hallucinations and falling asleep while performing activities of daily living. Rasagiline appears well tolerated, although adverse event rates are higher in the elderly. Hypertension may occur in the absence of interacting medications or diet. More commonly, hypertensive crisis may occur when MAOIs are ingested with high-content tyramine foods (>6-10 mg/serving). Transdermal selegiline at 6 mg/24 hours is void of this interaction although risk increases with higher doses. MAOIs are highly toxic in overdosage, affecting cardiac conduction and requiring hospitalization and careful monitoring while the drug is eliminated from the body. MOAIs bind monoamine oxidase irreversible and exert effects until monoamine is regenerated, which may require up to 14 days. MAOIs impair oxidative degradation of vasoactive amines and stimulant type medications. Hepatic enzyme inhibition (CPY2C19) increases serum levels of substrates (e.g. omeprazole, citalopram, sertraline) and the effect persists after the MAOI is discontinued. Caution is required in adding medications in patients who receive an MAOI or have had one recently discontinued. Of particular concern is the risk for serotonin syndrome. Use of an MAOI and additional medication which increases serotonin levels, especially one that increases serotonin by a different mechanism, may result in serotonin syndrome which may be fatal. Medications carrying the greatest risk in combination with an MAOI are the SSRIs and linezolid. The syndrome may occur in a dose-dependent fashion with the weak serotonin inhibitors meperidine, tramadol, methadone, fentanyl and dextromethorphan. Serotonergic interaction with the tricyclic antidepressants is greatest with clomipramine. Summary: The MAOIs are not first–line therapy for the treatment of depression as safer alternatives are available, although they may afford a benefit for patients with resistant or atypical depression. Comparative evidence is lacking for the nonselective MAOIs as well as the MAO-B inhibitors. Due to irreversible MAO-binding, caution must be exercised when using these medications.
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